Condition category
Nervous System Diseases
Date applied
04/01/2021
Date assigned
04/01/2021
Last edited
04/01/2021
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
COVID-19 patients frequently suffer brain problems during the infection and can be left with symptoms of brain injury. Similar problems have been seen in previous pandemics, including Spanish influenza over 100 years ago, but how and why this occurs is poorly understood.

The study will investigate the questions: in whom does COVID-19 cause injury? Does it do this by invading the brain? Or by triggering excessive immune responses or interfering with the blood supply to nervous tissue?

This study is a unique opportunity to understand how these problems occur and develop strategies to prevent and treat them.

Who can participate?
Adults admitted to a UK hospital during the COVID-19 pandemic suffering from both COVID-19 (by WHO criteria) and an acute neurological/psychiatric complication. The study team have been notified of 800 UK patients with these complications due to COVID-19. 500 control patients who had COVID-19 or other severe infections but did not develop brain complications will also be recruited. Participants will also be recruited prospectively in subsequent waves of infection.

What does the study involve?
The study team will conduct an in depth clinical, laboratory, and imaging study. The study will evaluate symptoms, signs, and brain function during hospitalisation and at follow-up (at 3 to 9 months). The study team will assess markers of brain injury, inflammation, and brain scan changes in these patients.

What are the possible benefits and risks of participating?
This study will be used to determine whether anti-viral medication, or treatments that modulate the immune system, or that improve blood supply, will help, and if so, in which patients.

This understanding will be applied through the COVID-Neuro Coalition Clinical Care Task Force to develop clinical care guidelines, identify patients for targeted clinical trials, and ultimately improve patient outcomes.

Where is the study run from?
Cambridge University Hospitals NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
From October 2020 to April 2022

Who is funding the study?
The Medical Research Council (UK)

Who is the main contact?
Dr Benedict Michael (Liverpool) and Prof Gerome Breen (KCL)
covidcns@liverpool.ac.uk

Trial website

http://covid-cns.org/

Contact information

Type

Scientific

Primary contact

Dr Benedict Michael

ORCID ID

http://orcid.org/0000-0002-8693-8926

Contact details

Clinical Infection Microbiology and Immunology
Ronald Ross Building
West Derby Street
Liverpool
L7 3EA
United Kingdom
+44 (0)7515404533
benmic@liv.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil Known

Protocol/serial number

MRC: MR/V03605X/1

Study information

Scientific title

Neurological and psychiatric complications of COVID-19 in hospitalised patients and the neurological, psychiatric and cognitive sequelae: the COVID-19 Clinical Neuroscience Study (COVID-CNS)

Acronym

COVID-CNS

Study hypothesis

1. Excluding recognised causes (e.g. hypoxia, medication), hospitalised COVID-19 patients who develop acute neurological complications are younger, have an abnormal Glasgow coma score on admission, and higher serum markers of inflammation, than hospitalised controls with/without COVID-19; and these patients have a worse medium-term neurological, cognitive and psychiatric outcome.
2. Hospitalised COVID-19 patients who develop acute neurological complications have a dysregulated pro-inflammatory immune response, driven by IL-1 and IL-6 rather than direct viral CNS infection.
3. Acute neurological complications are associated with an acute increase in serum markers of CNS injury and these markers in both acute and post-acute serum predict later sequelae. In some patients, new neurological complications later emerge or re-emerge in those with biomarker evidence of CNS injury or the development of antineuronal antibodies 12.
4. Similar, but milder neurological symptoms are reported in the community population who have had COVID-19 and are predicted by polygenic scores. If these scores are combined with CNS injury and inflammation markers they more accurately predict acute neurological complications of COVID-19.

Ethics approval

Pending 08/01/2021, ethical amendment to NIHR BioResource ethical approval (submission 8.1.21)

Study design

Multi-centre longitudinal case-control study

Primary study design

Observational

Secondary study design

Case-control study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a participant information sheet: covidcns@liverpool.ac.uk

Condition

Acute brain complications of COVID-19 and their neurological, psychiatric, and cognitive sequelae

Intervention

The study team have characterised the basic clinical details of 800 patients currently/recently hospitalised with COVID-19 with neurological complications from the CoroNerve and ISARIC -4C's studies. CoroNerve n=400, and ISARIC-4C’s n=400. 400 controls will be recruited form the ISARIC-4C’s trial and a further 100 will be recruited. Based on current data, approximately 20-30% will currently be hospitalised at initial data collection. Prospective participants will be recruited in subsequent waves of infection. All patients will be consented into existing NIHR BioResource infrastructure for long-term sustainability of follow-up.

Baseline assessment at admission will comprise of;
1. Acute Clinical Case Notes Review of Neurological Complications
2. Baseline data for demographics (including black and minority ethnicity background) and the index episode of acute neurological complication of COVID and previous history of neurological disorder, obtained by the Clinical Research Network (CRN) Nurses, supported by the study team:
2.1. Using the Brain Infections UK Case Record Form, from clinical case notes and routine test results
2.2. Neuroimaging files (estimated in 40-50% of cases, as CoroNerve over-represents patients under Neurologists and in large Neuroscience Units)
2.3. Retained serum (ISARIC-4C’s and local) and CSF (Co-I’s Neuroscience BioBanks)

Follow-up data will be obtained by face-to-face assessment at 3-9 months post-discharge for:
1. Neurology: Liverpool Brain Infectious Outcome Score and Neurological Impairment Scale mapped against functional outcomes.
2. Cognitive/psychiatric:
2.1. CNS-NeuroCog Protocol (built on UK BioBank, the MOCA/MMSE, CAMCOG, and CANTAB tools; piloted on 50).
2.2. NIHR BioResource COPING Protocol (an extended UK Biobank questionnaire covering neurological, cognitive, and psychiatry symptoms, already completed in >30,000).
3. Neuroimaging
4. Brain structural and functional connectivity changes will be measured by MRI in acute and post-infectious cases (compared to controls) and will be related both to blood immune and brain injury markers, and to distinct clinical phenotypes, thus providing a crucial explanatory link between biology and clinical features.

Intervention type

Other

Phase

Drug names

Primary outcome measure

1. Neuroglial injury markers (including Tau, NfL, GFAP, S100, and NSE) measured using quantitative analysis of plasma at baseline (admission) and follow-up (at 3 to 9 months post-discharge)

Secondary outcome measures

1. Cytokine/chemokine profiles measured by luminex from samples at baseline and follow-up
2. Volume of T2 FLAIR signal measured from brain magnetic resonance imaging at baseline and follow-up

Overall trial start date

31/10/2020

Overall trial end date

30/04/2022

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Cases and controls:
1. Aged >17 years
2. Admitted to a UK hospital during the COVID-19 pandemic
3. Suffering from COVID-19 (by WHO definitions. ‘Confirmed’: Positive PCR of respiratory samples or serology and ‘Probable’ by chest radiograph/CT evidence of COVID-19 but PCR/serology negative or not tested)

Cases only
1. Suffering from an acute neurological/psychiatric complication (e.g. encephalitis, unexplained [e.g. non-hypoxic] encephalopathy/delirium, and stroke without major risk factors).

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

1,400

Participant exclusion criteria

Does not meet inclusion criteria

Recruitment start date

01/02/2021

Recruitment end date

30/04/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University of Liverpool
West Derby Street
Liverpool
L7 3EA
United Kingdom

Trial participating centre

King's College London
Strand
London
WC2R 2LS
United Kingdom

Trial participating centre

Cambridge University
Trinity Lane
Cambridge
CB2 1TN
United Kingdom

Sponsor information

Organisation

Cambridge University Hospitals NHS Foundation Trust

Sponsor details

Hills Road
Cambridge
CB2 0QG
United Kingdom
+44 (0)1223245151
jrb1000@cam.ac.uk

Sponsor type

Hospital/treatment centre

Website

http://www.cuh.org.uk/

Funders

Funder type

Government

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

UK Research and Innovation

Alternative name(s)

UKRI

Funding Body Type

private sector organisation

Funding Body Subtype

Other non-profit organizations

Location

United Kingdom

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal. Raw data for proteomic and immunological data will be made available, upon publication in existing open access repositories as required by the WHO and ICMJE.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

30/04/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

04/01/2021: Trial’s existence confirmed by the National Institute for Health Research (NIHR).